Elucidation of the methylerythritol phosphate pathway for isoprenoid biosynthesis in bacteria and plastids. A metabolic milestone achieved through genomics.
AuthorsRodríguez-Concepción M, Boronat A
JournalPlant Physiol
PubMed ID12427975
Pharmacokinetics of fosmidomycin, a new phosphonic acid antibiotic.
AuthorsMurakawa T, Sakamoto H, Fukada S, Konishi T, Nishida M
JournalAntimicrob Agents Chemother
PubMed ID7073262
'The pharmacokinetics of fosmidomycin was investigated in animals and humans after parenteral and oral dosing. In dogs the serum concentration was 54.8 microgram/ml at 0.25 h after an intravenous dose of 20 mg/kg, and the half-life was 1.14 h. Peak concentration was 41.4 microgram/ml after an intramuscular dose of 20 ... More
Cross-talk between the cytosolic mevalonate and the plastidial methylerythritol phosphate pathways in tobacco bright yellow-2 cells.
AuthorsHemmerlin A, Hoeffler JF, Meyer O, Tritsch D, Kagan IA, Grosdemange-Billiard C, Rohmer M, Bach TJ
JournalJ Biol Chem
PubMed ID12736259
'In plants, two pathways are utilized for the synthesis of isopentenyl diphosphate, the universal precursor for isoprenoid biosynthesis. The key enzyme of the cytoplasmic mevalonic acid (MVA) pathway is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR). Treatment of Tobacco Bright Yellow-2 (TBY-2) cells by the HMGR-specific inhibitor mevinolin led to growth reduction and ... More
Diaryl ester prodrugs of FR900098 with improved in vivo antimalarial activity.
AuthorsReichenberg A, Wiesner J, Weidemeyer C, Dreiseidler E, Sanderbrand S, Altincicek B, Beck E, Schlitzer M, Jomaa H
JournalBioorg Med Chem Lett
PubMed ID11277531
'The fosmidomycin derivative FR900098 represents an inhibitor of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase with potent antimalarial activity. Prodrugs of FR900098 with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield phosphodiaryl esters. One diaryl ester prodrug demonstrated efficacy in mice infected with the ... More
Mevalonate and nonmevalonate pathways for the biosynthesis of isoprene units.
AuthorsKuzuyama T
JournalBiosci Biotechnol Biochem
PubMed ID12353619
'Isoprenoids are synthesized by consecutive condensations of their five-carbon precursor, isopentenyl diphosphate, to its isomer, dimethylallyl diphosphate. Two pathways for these precursors are known. One is the mevalonate pathway, which operates in eucaryotes, archaebacteria, and cytosols of higher plants. The other is a recently discovered pathway, the nonmevalonate pathway, which ... More
Tools for discovery of inhibitors of the 1-deoxy-D-xylulose 5-phosphate (DXP) synthase and DXP reductoisomerase: an approach with enzymes from the pathogenic bacterium Pseudomonas aeruginosa.
AuthorsAltincicek B, Hintz M, Sanderbrand S, Wiesner J, Beck E, Jomaa H
JournalFEMS Microbiol Lett
PubMed ID11034300
'Two Pseudomonas aeruginosa genes encoding the enzymes 1-deoxy-D-xylulose 5-phosphate (DXP) synthase and DXP reductoisomerase, both involved in the mevalonate-independent biosynthesis of isoprenoids, have been expressed as recombinant enzymes in Escherichia coli. The purified P. aeruginosa DXP reductoisomerase was inhibited by submicromolar concentrations of the antibiotics fosmidomycin and FR-900098 in a ... More
Synergy of fosmidomycin (FR-31564) and other antimicrobial agents.
AuthorsNeu HC, Kamimura T
JournalAntimicrob Agents Chemother
PubMed ID7181471
'Fosmidomycin (FR-31564), a phosphonic acid derivative, was combined with cefazolin, cephalexin, ampicillin, carbenicillin, ticarcillin, gentamicin, and trimethoprim. Synergy between fosmidomycin and penicillins or cephalosporins was found for 37 to 52% of the Enterobacteriaceae tested. Synergy with trimethoprim was found against 55% of bacteria isolated, but only 17% of the strains ... More
Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs.
AuthorsJomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, Türbachova I, Eberl M, Zeidler J, Lichtenthaler HK, Soldati D, Beck E
JournalScience
PubMed ID10477522
'A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. ... More
Recent developments in the field of phosphonic acid antibiotics.
AuthorsNeuman M
JournalJ Antimicrob Chemother
PubMed ID6501127
Studies on phosphonic acid antibiotics. IV. Synthesis and antibacterial activity of analogs of 3-(N-acetyl-N-hydroxyamino)-propylphosphonic acid (FR-900098).
AuthorsHemmi K, Takeno H, Hashimoto M, Kamiya T
JournalChem Pharm Bull (Tokyo)
PubMed ID7083400
Planting the seeds of new antimalarial drugs.
AuthorsRidley RG
JournalScience
PubMed ID10498534
Studies on new phosphonic acid antibiotics. II. Taxonomic studies on producing organisms of the phosphonic acid and related compounds.
AuthorsIguchi E, Okuhara M, Kohsaka M, Aoki H, Imanaka H
JournalJ Antibiot (Tokyo)
PubMed ID7372546
A new species of Streptomyces which produces a new cell wall-inhibitory antibiotic, FR-900098 containing phosphonic acid in its molecule, is named and described. The species name proposed, Streptomyces rubellomurinus, refers to the aerial mass color. Streptomyces rubellomurinus subsp. indigoferus also produces FR-900098 and the related compound FR-33289. FR-900098 related compounds, ... More
Studies on new phosphonic acid antibiotics. III. Isolation and characterization of FR-31564, FR-32863 and FR-33289.
AuthorsOkuhara M, Kuroda Y, Goto T, Okamoto M, Terano H, Kohsaka M, Aoki H, Imanaka H
JournalJ Antibiot (Tokyo)
PubMed ID6768705
Three phosphonic acid antibiotics were found to be produced in the fermentation broths of Streptomyces. FR-31564 and FR-32863 were produced by Streptomyces lavendulae. FR-33289 was produced by a strain of Streptomyces, identified as Streptomyces rubellomurinus subsp. indigoferus. They are distinct from, but resemble FR-900098 which was reported in our preceding ... More
Studies on new phosphonic acid antibiotics. I. FR-900098, isolation and characterization.
AuthorsOkuhara M, Kuroda Y, Goto T, Okamoto M, Terano H, Kohsaka M, Aoki H, Imanaka H
JournalJ Antibiot (Tokyo)
PubMed ID6768704
A strain of Streptomyces, isolated from a soil sample and identified as Streptomyces rubellomurinus sp. nov., has been found to produce FR-900098, an interesting new antibiotic containing phosphorus in its molecule. The antibiotic, obtained as colorless crystals, was shown to inhibit a wide variety of Gram-negative bacteria including Pseudomonas, Proteus, ... More
Acyloxyalkyl ester prodrugs of FR900098 with improved in vivo anti-malarial activity.
AuthorsOrtmann R, Wiesner J, Reichenberg A, Henschker D, Beck E, Jomaa H, Schlitzer M
JournalBioorg Med Chem Lett
PubMed ID12798327
FR900098 represents an improved derivative of the new antimalarial drug fosmidomycin and acts through inhibition of the 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Prodrugs with increased activity after oral administration were obtained by chemical modification of the phosphonate moiety to yield ... More
Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered ... More
Role of the non-mevalonate pathway in indole alkaloid production by Catharanthus roseus hairy roots.
AuthorsHong SB, Hughes EH, Shanks JV, San KY, Gibson SI
JournalBiotechnol Prog
PubMed ID12790690
The 1-deoxy-D-xylulose-5-phosphate (DXP) pathway (non-mevalonate pathway) leading to terpenoids via isopentenyl diphosphate (IPP) has been shown to occur in most bacteria and in all higher plants. Treatment with the antibiotic fosmidomycin, a specific inhibitor of DXP reductoisomerase, considerably inhibited the accumulation of the alkaloids ajmalicine, tabersonine, and lochnericine by Catharanthus ... More
Inhibition of paclitaxel and baccatin III accumulation by mevinolin and fosmidomycin in suspension cultures of Taxus baccata.
AuthorsPalazón J, Cusidó RM, Bonfill M, Morales C, Piñol MT
JournalJ Biotechnol
PubMed ID12568744
To achieve a better understanding of the metabolism and accumulation of paclitaxel and baccatin III in cell cultures of Taxus, inhibitors of the early steps in the terpenoid pathway were applied to a cell suspension culture of Taxus baccata: fosmidomycin as an inhibitor of the non-mevalonate branch of the pathway, ... More
Pharmacokinetics and metabolism of fosmidomycin, a new phosphonic acid, in rats and dogs.
AuthorsTsuchiya T, Ishibashi K, Terakawa M, Nishiyama M, Itoh N, Noguchi H
JournalEur J Drug Metab Pharmacokinet
PubMed ID7067725
The absorption, distribution, metabolism, and excretion of 3-(N-formylhydroxylamino) propylphosphonic acid monosodium salt (fosmidomycin), a new antibiotic, were investigated in rats and dogs after i.v. and oral dosing. After i.v. administration of 10 mg/kg of body weight, [14C]-fosmidomycin was excreted mainly in the urine (about 90% of dose within 72 h); ... More
Fosmidomycin, a novel chemotherapeutic agent for malaria.
AuthorsLell B, Ruangweerayut R, Wiesner J, Missinou MA, Schindler A, Baranek T, Hintz M, Hutchinson D, Jomaa H, Kremsner PG
JournalAntimicrob Agents Chemother
PubMed ID12543685
In previous studies, fosmidomycin has been shown to possess activity against Plasmodium falciparum in vitro and in the mouse model. It has a novel mode of action through inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this open-label, ... More